Our goal is to develop platform technologies that solve fundamental problems in biomedicine. Certainly one of the major problems is the targeted delivery of genes and drugs to the appropriate cells in vivo. The study and treatment of diabetes exemplifies this need. While there have been important studies in understanding the metabolism and regulation in beta-islet cells, the next phase of understanding will pivot on being able to deliver specific genes and drugs to these cells in vivo in various genetic backgrounds. This delivery technologies will also be required for any practical gene therapy protocols. Our aim is to develop technologies that allow delivery of genes, peptides, or small molecules to beta-cells in vivo. These techniques will complement and enhance the basic research projects in this program. Our plan is to accomplish these goals in the following. First we will employ our phage library planning techniques to isolate peptides that specifically bind to and enhance uptake into beta-islet cells. The libraries will be panned both in vitro on cell lines and isolated cells and in vivo in rats. If in vivo panning works, i.e. phage can access islets, we will launch a second effort to develop phage themselves as delivery vehicles, for genes, peptides, proteins and small molecules. Third, whether the phage can be used in vivo or not, we will improve the peptides by rational design and mutagenesis to increase both their selective and specific uptake into beta-cells. Fourth, non-phage delivery systems will be developed where the targeting peptides are attached to genes, proteins or small molecules. All of these delivery strategies will be evaluated in vivo in the rat. Finally, we will explore a novel physical approach to targeting that employs ultrasound to burst microbubbles in specific areas of the intact animal. Microbubbles coated with adenovirus or phage will be developed as an adjuvant to the vector targeting strategy. Together these platform technologies should afford new methods to explore the basis and cures for diabetes as well as be applicable to many other areas of biomedicine.